Hydroxyphenalkylaminoalkylindoles and ethers corresponding thereto



United States Patent HYDROXYPHENALKYLAMINOALKYLINDOLES AND ETHERS CORRESPONDING THERETO Richard A. Robinson, Evanston, Ill., assignor to G. D. Searle & Co., Chicago, Ill., a corporation of Delaware No Drawing. Application July 14, 1958 Serial No. 748,545

9 Claims. (Cl. 260319) This invention relates to hydroxyphenalkylaminoalkylindoles, and ethers corresponding thereto. More particularly, this invention relates to products of the formula I wherein Z and Z' are each hydrogen or an optionallyetherified hydroxyl radical, Alk is an alkylene or hydroxyalkylene radical, and R is hydrogen or an etherifying moiety.

The substituent ether groupings referred to by, Z, Z', and OR in theforegoing formula arepreferably hydrocarbonoxylradicals, either saturated or aromatic, which containfewer :than 9 carbon atoms. Examples of such radicals are-lower alkoxy groupings as also cyclopentyloxy, cyclohexyloxy, and benzyl radicals. Those' skilled in the art will appreciate that lower alkyl radicals include methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, tert-pentyl, neopentyl hexyl, isohexyl, heptyl, octyl, and like C H groupings wherein n is a positive integer amounting to not more than 8.

The alkylene radicals called for by Alk in the generic formula for compounds of this'invention are desirably those comprising more than l and less than 5 carbon atoms, illustratively,

1,2-ethylene CH' CH Trimethylene cH cH,cH,

, v V l 2-methyl-1,2-propylene (OH1(|J CH I and like bivalent, saturated, acyclic, straightor branchedchain, hydrocarbon groupings. The alkylene radicals comprehended by Alk' diflier, as a class, only in being made up of fewer than 4 carbon atoms, while the hydroxyalkylene radicals embraced by Alk' are C -C alkylene groupings wherein at least 1 hydrogen is replaced by hydroxyl.

The application for Letters Patent securing the inven-- tion herein described and claimed is a continuation-in-part of applicants prior copending application, Serial No.

610,898, filed September 20, 1956, now abandoned.

Equivalent to the foregoing basic amines for the pinproximately stoichiometrically equivalent I When the catalyst used is platinum oxide, there is also 2,998,691 Patented Oct. 13, 1959 poses he're described are non-toxic acid addition salts thereof, the composition of which may be symbolized by anti-secretory agents, effective in reducing gastric acidity.

In addition, they exhibit valuable elfects on the central nervous system, being possessed of anti-emetic properties and a capacity to potentiate the action of barbiturates in maintaining a state of hypnosis.

Manufacture of the claimed compositions proceeds by reductive amination of a carbonyl compound of the formula Oarb with an amine of the formula in a solvent such as a lower alkanol, the terms Z, Z, A111,

and R being defined as above and Carb being identical with Alk except that 1 oxygen replaces 2 hydrogens on the carbon thereof which attaches to nitrogen. This reaction is carried out, for example, by shaking a solution of the carbonyl compound and the phenolic amine in methanol in the presence of a hydrogen atmosphere and a hydrogenation catalyst, suitably a noble metal catalyst such as platinum oxide. The reaction can also be carried out stepwise by first forming the condensation product of the carbonyl compound and the phenolic amine and then conducting the hydrogenation as a separate operation.

The reductive aminations herein described are satisfactorily etfected at room temperatures under approximately 1 to 5 atmospheres of hydrogen pressure. As is well known in the art, a hydrogenation reaction sometimes exhibits irregular behavior in starting because of such factors as impurities in the solvents or reagents, the presence of catalyst poisons, variations in activity of particular batches of catalysts, etc. Accordingly, while typical reaction times under normal conditions have been included in many of the examples hereinafter, the period of time required for completion of the reaction is more accurately determined by measuring the consumption of hydrogen rather than by conducting the reduction for an arbitrary period of time. In the reductive aminations described herein there is consumed a total of approximately 1 molecular equivalent of hydrogen for each molecular equivalent of either the amine or the carbonyl compound when these 2 reactants are employed in apquantities.

to reductive amination with an amine of the formula in accordance with the techniques previously described, Z, Z, Alk, and R having the same meanings as before,

, and Carb being identical with Alk except that 1 oxygen replaces 2 hydrogens on the carbon thereof which attaches to nitrogen.

Still another means of producing the compositions of this invention, and 1 wherein hydrogenation plays no part, is the condensation of a halogen derivative of the type with an amine of the formula Z, Z, Alk, Alk, and R being as before.

The products which have free phenolic hydroxyls can also be obtained by the cleavage of the corresponding alkyl ethers with pyridine hydrochloride, or by catalytic hydrogenation of the corresponding benzyl ethers. The latter operation is particularly useful for the conversion of compounds of the invention wherein Z is a benzyloxy substituent to those wherein Z is OH.

Conversion of the amine bases of this invention to corresponding acid addition salts is accomplished by simple admixture of these compounds with 1 equivalent of any of various inorganic and strong organic acids, the anionic portion of which conforms to X as hereinbefore defined.

The following examples described in detail certain of the compounds illustrative of the present. invention and methods which have been devised for their manufacture. However, the invention is not to be construed as limited thereby, either in spirit or in scope, since it will be apparent to those skilled in the art of organic synthesis that many modifications, both of materlals and of methods, may be practiced without departing from the purpose and intent of this disclosure. In the examples hereinafter detailed, temperatures are given in degrees centigrade, pressures in millimeters of mercury, and relative amounts of material in parts by weight, except as otherwise noted.

Example 1 (A) 3 {2 [2 (3,4 dimethoxyphenyl) 1 (methyl) ethylamin0]ethyl}ind0le oxalate.--Activated charcoal is digested in dilute aqueous nitric acid and then Washed consecutively with water and ethanol. A suspension of 6 parts of this charcoal in a solution of 2 parts of palladium chloride in 1000 parts of aqueous 50% tion and washed consecutively with water and ethanol, whereupon it is suspended in 800 parts of methanol and agitated thus under a hydrogen atmosphere at approximately 25 for 1 hour.

An intimate mixture of 58 parts of tryptamine and parts of 3,4-dimethoxyphenyl-2-propanone is heated at 100 for 1 hour, following which it is dissolved in approximately 800 parts of methanol. This solution is combined with the methanol suspension of catalyst derivedby the procedure of paragraph one in this example; and the resultant mixture is agitated under a hydrogen atmosphere for approximately 5 hours. The mixture is then filtered, and to the filtrate is added a solution of approximately 17 parts of oxalic acid in parts of methanol. The crystalline precipitate thrown down is collected on a filter. This material is 3-{2-[2-(3,4-dimethoxyphenyl) 1 (methyl)ethylamino]ethyl} indole oxalate, which melts at approximately 226 and has the formula 0001-1 CHzCHzNHCHCH 0CH3-| coon on, A)

(B) 3 {2 [2 (3,4 dimethoxyphenyl) 1 (methyl)-ethylamin0]ethyl}ind0le.-A suspension of the oxalate of the foregoing part A of this example in dilute aqueous sodium hydroxide is extracted with ether. The ethereal extract is dried over potassium hydroxide and then stripped of solvent by distillation under reduced pressures. The residue is the free base, 3-{2-[2-(3,4-di- 'rnethoxyphenyl) 1 (methylethylaminolethyl}indole.

(C) 3' {2 [2 (3,4 dimethoxyphenyl) 1 (methyl) ethylamin0]ethyl}ind0le hydrochloride.-An ether solution of the free baseof the preceding part B of this example is treated with a slight excess of hydrogen chloride dissolved in 2-propanol. The crystalline precipitate which forms is 3-{2-[2-(3,4-dimethoxyphenyl)-l-(methyl)-ethylaminolethyl}indole hydrochloride, the melting point, of which is approximately 184. The product is isolated by filtration.

Example 2 (A) 3 {2 [2 (3,4 dihydroxyphenyl) 1 (methyl) ethylaminolethyl}indole hydrochloride.-An intimate mixture of 31 parts of 3-{2-[2-(3,4-dimethoxyphenyl)-l- (methyl)ethylamino]ethyl}indole and parts of pyridine hydrochloride is heated in a nitrogen atmosphere for 4 hours at l90210. The reaction mixture is then cooled and mixed with sufiicient chloroform to dissolve the pyridine hydrochloride which has not been lost by sublimation during the heating period. Under typical conditions, about 3000 parts of chloroform is employed. The chloroform phase is discarded and the oily supernatant layer taken up in about 30 parts of water. This solution is washed with ether and then treated with an excess of hydrochloric acid. Crystallization is induced, the crystalline product being filtered off and washed with a minimum quantity of water, and then with acetone. The product thus obtained is 3-{2-[2-(3,4-dihydroxyphenyl) 1 (methylethylaminoJethyl}indole hydrochloride, the melting point of which is approximately 242.

methanol containing a small amount of hydrochloric acid is agitated under a hydrogen atmosphere at approximately 25 until hydrogenation is complete. The resultant palladium-on-charcoal catalyst is isolated by filtra- The product has the formula omommapnon-onnm CH3 i I OH (B). 3 {2 [2 (3,4 dihydroxyphenyl) 1 (methyl)-ethylamino]ethyl}indole.A solution of the hydrochloride of the preceding part A of this example in aqueous methanol is added, with agitation, toan excess about 5 hours.

of sodium bicarbonate dissolved in water. Agitation is continued for about 30 minutes, after which the crystalline base which precipitates is filtered out and washed consecutively with water, propanol, and methanol. The 3 {2 [2 (3,4 dimethoxyphenyl( 1 (methyDethylaminolethyl}indole thus obtained is a colorless product melting at approximately 191.

Example 3 3 {2 [2 (3,4 dibenzyloxy) 2 hydroicy 1- (methyl) ethylamino] ethyl}indole oxalate.A solution of 120 parts of 1-(3,4-dibenzyloxyphenyl)-l-hydroxy=2-propanone and 5 3 parts of tryptamine in 240 parts of methanol is mixed with 1 part of platinum oxide and agitated under hydrogen at pressures of the order of 30-40 pounds per square inch at 25 for about 3 hours, 1 equivalent of hydrogen being absorbed in this time. The mixture is then filtered, and the filtrate is freed of solvent by distillation. To' the residue is added 1 molar equivalent of oxalic acid dissolved in ethanol. The crystalline oxalate which forms is recovered from the mother liquors by filtration. The material thus isolated is 3-{2-[2-(3,4-dibenzyloxy)-2-hydroxy-1-(methyl)- ethylamino]ethyl}indole oxalate, of the formula omomNHoHoHoH oomQ Example 4 Y 3 {2 [2 hydroxy 2 (3,4 dihydroxyphenyl) 1- (methyl)ethylaminolethylfindole oxalate.A solution of 40 parts of the oxalate of the preceding Example 3 in 400 parts of methanol is hydrogenated at atmospheric i omommzononon-Qon 10011 ooon Example 5 (A) a-Methyl-3-indoleethanol.-To a solution of approximately 29 parts of methyhnagnesium bromide in Y 150 parts of anhydrous ether, maintained 'With agitation at approximately 0, there is added over a period of about 1 hour a solution of 24 parts of indole in 45 parts of anhydrous ether. After a further 45 minutes, a solution of 13 parts of propylene oxide in 55 parts of anhydrous benzene is introduced during 30 minutes. Throughout the foregoing operations and for an additional 2 hours, the reactants are maintained at temperatures of' the order of 05 with agitation. Thereafter, the reaction mixture is allowed to warm to room temperatures and then distilled at a rate such that substantially all of the ether and benzene are removed during a period of The residual mass is decomposed with ice water. Solid carbon dioxide is added to dissolve the .magnesium, following which the mixture is extracted .with several portions of ether. washed'with water, dried over anhydrous sodium sulfate,

and distilled under reduced pressuresto give a fraction The ether extracts are 6 boiling at l45/0.15 mm., which is a-methyl-3-indole ethanol; 1

(B) 3-(2-br0ni0pr0pyl) inddle.-A mixture of 42 parts of wmethyl-3-indoleethanol, 21 parts of phosphorus tribromide, and 1200 parts of chloroform is maintained in a nitrogen atmosphere at about 25 for 15 hours, after which the solvent is removed by distillation in vacuo. The non-volatile residue is 3-(2-bromopropyl)indole; I 1 (C) 3 {2 [2-(3,4-dimeth0xyphenyl)ethylaminolpropyl} indole hydrochloride-To a solution of approximately 32 parts of 3-(2-bromopropyl)indole in 350 parts of ether is added 45 parts of 3,4-dimethoxyphenethylamine. The resultant mixture is heated until the solvent is distilled off, following which it is maintained in the range -100" for an additional 2 hours. The mixture is then taken up in 750 parts of chloroform, and the resultant solution is washed with a total of 400 parts of water in 4 portions. (Unreacted 3,4-dimethoxyphenethylamine is recovered as the hydrobromide by evaporation of the aqueous washes.) The chloroform solution is freed of solvent by distillation and the residue is partitioned into a relatively soluble component and a relatively insoluble component by extracting it with approximately 200 parts of aqueous 5% hydrochloric acid. The relatively insol- COOH COOH

aqueous hydrochloric acid. The product is obtained thus,

as a hydrate melting at 125l28, which is converted to the anhydrous form melting at 152-153 by drying in vacuo over phosphorus pentoxide at The product has the formula CHgC|1HNHOHiCHrO CH; .1101

CH: 60H;

Example 6 3-{2-[2-(3,4-dihydr0xyphenyl) ethylamino] propyl}- indole hydrochloride-Treatment of 3-{2-[2-(3,4-dimeth oxyphenyl)ethylamino]propyl}indole hydrochloride with pyridine hydrochloride in accordance with procedure detailed in Example 2A hereinbefore effects damethylation thereof and affords 3-{2-[2-(3,4-dihydroxyphenyl)ethylamino] propyl}indole hydrochloride, of the formula Example 7 3-{2-[2-hydr0xy-2-(3,4 dihydroxyphenyl) ethylamino] propyl}indole tartrate.--A mixture of approximately 52 parts of 1-(3-indolyl) -2-propanone and 51 parts of u,3,4-trihydroxyphenethylamine is dissolved in 600 parts of methanol. Approximately 1 part of platinum oxide is suspended in this solution, and the resultant mixture is agitated at 25 under hydrogen at pressures of the order of 3040 pounds per square inch. Hydrogen absorption, rapid at first, becomes progressively slower, approximately 3 hours being required for the uptake of 1 molecular equivalent of the gas. At this point, catalyst is filtered ofli; and the filtrate is stripped of solvent by vacuum distillation at room temperatures. The residue is dissolved in 2-propanol and treated with 1 molar equivalent of tartaric acid. The acid addition salt thus formed is soluble in 2-propanol, wherefore ether is added to efiect precipitation. The precipitate is recovered on a filter, washed with ether, and dried in vacuo over phosphorus pentoxide. This material is 3-{2-[2-hydroxy-2-(3,4-dihydroxyphenyl)ethylamino]propyl}indole tartrate, which is moderately hygroscopic, and melts undefinitely beginning at around 65 The product has the formula Example 8 3 {2 [2-(3,4-dimeth0xyphenyl) 1 (methyl)-ethylaminolpropyl}indle hydr0chl0ride.To a solution of 6 parts of 3-(2-bromopropyl)indole in 75 parts of other is added 10 parts of 3,4-dimethoxy-a-methylphenethylamine. The resultant mixture is heated at a rate such that substantially all of the other is removed by distillation during a 2-hour period, following which the residue is heated at 90l00 for an additional hour. The residue is then taken up in 750 parts of chloroform, and this solution is washed with a total of 300 parts of aqueous 50% methanol in 2 portions. (By evaporation of the methanolic wash water, unused 3,4-dimethoxy-a-methylphenethylamine is recovered as the hydrobromide.) The chloroform solution is stripped of solvent by distillation, and the residue is taken up in ether. Addition to this solution of a slight excess of hydrogen chloride dissolved in 2-propanol causes precipitation of a product which is fractionated into 2 components having greater and lesser degrees of solubility in water on extraction with about 100 parts thereof. The relatively insoluble component, which is customarily the principal fraction, is suspended in an excess of dilute aqueous sodium hydroxide; and the free base which is thrown down is extracted with several portions of benzene. The benzene extracts are combined and chromatographed on alumina, using benzene and acetone as developing solvents. 3-{2-[2-(3,4-dimethoxyphenyl)- 1-(methyl)ethylaminolpropyl}indole is eluted at a satisfactory rate with solutions of acetone in benzene containing about 20 to 50% (by volume) of acetone. The base appears as a principal weight peak in the elution curve, and the corresponding eluate residues obtained on evaporation of solvent are dissolved in ether and treated with a slight excess of hydrogen chloride in 2-propanol solution. There is obtained by this means the desired 3-{2- [2-(3,4 dimethoxyphenyl)-1-(methyl)ethylamino] propyl} indole hydrochloride melting at 85-90". After thorough drying, this melting point is increased to approximately 95 or higher. 3-{2-[2-(3,4-dimethoxyphenyl)-l-(methyl)ethylamino]propyl}indole hydrochloride has the formula OCH;

- Example 9 of platinum oxide in 600 parts of methanol. The resulting mixture is agitated in a hydrogen atmosphere at 25 for about 4 hours, whereupon the catalyst is removed by filtration and the filtrate is stripped of solvent by distillation. The oil which remains is dissolved in 3600 parts of anhydrous ether. The ethereal solution is mixed with 50 parts of carbon disulfide and allowed to stand for around 20 hours at room temperatures. The gummy dithiocarbamate which-precipitates is collected on a filter and dissolved in 2-propanol. To this solution, an excess of hydrogen chloride in 2-propanol is added, followed by sufficient anhydrous ether to induce precipitation. The precipitate so produced is collected on a filter and washed consecutively with ether and dilute aqueous hydrochloric acid. Recrystallization from water containing a small amount of methanol affords pure 3-{3-[2-(3,4-dimethoxyphenyl)ethylamino]butyl}indole hydrochloride, melting at 168170, and having the formula Example 10 N1 l i CH OHzCfI-INHCHzCHzQ-OH (B) 3 {3 [2 (p-hydroxyphenyl)ethylamino] butyl} indole hydrochloride-A solution of the base of the preceding part A of this example in 2-propanol is precipitated with a slight excess of 2-propanolic hydrogen chloride. This precipitate, recovered on a filter and recrystallized from dilute aqueous hydrochloric acid, melts at approximately 203. The material thus obtained is 3 {3 [2 (p-hydroxyphenyl)ethylarnino]butyl}indole hydrochloride.

Example 11 (A) 5 mathoxy 3 {2 [2-(3,4 dimethoxyphenyD- ethylamino]ethyl}indole.A reaction mixture prepared from approximately 19 parts of 3,4 dimethoxyphenylacetaldehyde, 19 parts of S-methoxytryptamine, 1 part of platinum oxide catalyst transferred under anhydrous ethanol, and 1200 parts of methanol is agitated in contact with a hydrogen atmosphere for 2 hours at approximately 25. The catalyst is removed by filtration, and the filtrate is stripped of solvent by distillation in vacuo.

. tures.

The residue is 5-methoxy-3-{2-[2-(3,4-dimethoxyphenyl)r ethy1amino]ethyl}indole of the formula I vH Eco l omomrmcu'muQ-oom (B) 5 methoxy -3 {2 [2 (3,4 dimethoxyphenyD- ethylamino] ethyl}indle hydrobromide.-A solution of the free base of the foregoing part A of this example in ether is treated with a slight excess of hydrogen bromide in 2-propanol, and the precipitated product is collected and Washed with ether. This product is -methoxy-3-{2- [2-( 3 ,4-dimethoxyphenyl) ethylamino] ethyl}indole hydrobromide.

(C) 5 methoxy 3 {2 [2 (3,4 dimethoxyphenyl)ethylamino]ethyl}ind0le citrate.-The citric acid salt of the base of the foregoing part A of this example is obtained by treating a solution of 7 parts of the free base in a minimum quantity of methanol with a solution of approximately 4 parts of citric acid in methanol, and evaporating the resultant mixture to a small volume. The precipitate thereupon thrown down is 5-methoxy-3- {2- [2-( 3 ,4-dimethoxyphenyl) ethylamino] ethyl}indole citrate.

Example 12 (A) 6 methoxy 3 {2 [2 (3,4 dimeth0xyphenyl)-1-(methyl) ethylamino] ethyl}ind0le.-A mixture of 60 parts of 3,4-dimethoxyphenyl-Z-propanone, 57 parts of 6-methoxytryptamine, 3 parts of platinum oxide catalyst dispersed in 160 parts of anhydrous ethanol, and 1600 parts of methanol is agitated in contact with a hydrogen at about 25.

10- Example 13 5 ethoxy 3 {2 [2 3,4 dimethoic'yph'nyl) e 1 -(methyl ethylamino] ethyl} indole.--Using the procedure of Example 12(A) hereinabove, but substituting 61 parts of S-ethoxytryptamine for the 57 parts of 6-methoxytryptamine called for therein, there is obtained S-ethoxy- 3.- {2 [2 (3,4 dimethoxyphenyl) 1 (methyl)ethylamino]ethyl}indole, which has the formula H5030 CH CHgNHCEhCHr OCH;

OCH;

Example 14 (A) 5 benzyloxy 3 {2 [2 (3,4 dimethoxyphenyl)-]-(methyl)ethylamin0]ethyl}indole 0xal ate.-A mixture of parts of S-benzyloxytryptamine, 34 parts of 3,4-dimethoxyphenyl-2-propanone, 2 parts of platinum oxide catalyst, and 2000 parts of methanol is agitated in contact with a hydrogen atmosphere for 1 hour An additional 20 parts of 3,4-dimethoxyphenyl-Z-propone is added, and hydrogenation is continued for an additional hour, after which the catalyst is removed by filtration and the filtrate is treated with approximately 8 parts of oxalic acid. Solvent is removed by vacuum distillation, and the crystalline residue is washed with ether and then recrystallized from methanol. The product thus obtained is 5-benzyloxy-3-{2-[2-(3,4- dimethoxyphenyl) 1 (methyl)ethylamino]ethy1}indole oxalate, melting at approximately 179-180, and having the formula r atmosphere for approximately 3 hours at room tempera- The catalyst is removed by filtration, and the filtrate is stripped of solvent by vacuum distillation. The residue thus obtained is 6-methoxy-3-{2-[2-(3,4-dimethof the formula I on,

(B) 6 methoxy 3 {2 [2 (3,4 dimethoxyphenyD-l-(methyl)ethylamino]ethyl}ind0le hydrochloride-A solution of the free base of the foregoing part A of this example in ether is treated with an excess of hydrogen chloride in 2-propanol. The productwhich precipitates is collected on a filter and washed with ether.

This product is the water-soluble, hygroscopic hydrochloride of 6 methoxy 3{2 [2 (3,4 dimethoxyphenyl) -1- (methyl) ethylarnino] ethyl}indole.

(C) 6 methoxy 3 {2 [2 (3,4 dimethoxyphenyl) -1-(methyl) cthylamino] elhyl}indole 0xalate.A solution of parts of the free base of the preceding part A of this example in 5700 parts of other is mixed with 16 parts of oxalic acid, and the insoluble product thrown down is collected and washed with ether. This product is suspended for several minutes in Warm acetone, recovered by filtration, andpurified by recrystallization from methanol. There is obtained by this means 6-methoxy-3- {2 [2 (3,4 dirnethoxyphenyl) 1 (methyl)ethylamino]ethyl}indole oxalate, which melts at about 203- 204. 7

(B) 5 benzyloxy 3-{2-[2-(3,4-dimethoxyphenyl)-1- (methyl)ethylamino]ethyl}ind0le.A suspension of the oxalate of the foregoing part A of this example in dilute aqueous sodium hydroxide is extracted with ether, and the ethereal solution is washed with water and stripped of solvent by distillation under reduced pressures. The

COOH

Example 15 (A) 5 hydroxy 3-{2-[2-(3,4-dimeth0xy phenyl)-1- (methyl)ethylamino]ethyl}ind0le 0xalate.-A hydrogenation catalyst is prepared by suspending 6 parts of activated charcoalwhich has previously been digested in dilute nitric acid and subsequently washed consecutively water and ethanol-in a solution of 2 parts of palladlum chloride in 1000 parts of water containing a small amount of hydrochloric acid, and shaking the resulting suspension in contact with a hydrogen atmosphere at room temperatures until hydrogenation is complete. The palladium-on-charcoal catalyst is recovered by filtration and washed consecutively with water and ethanol, following which it is suspended in 2000 parts of methanol. This suspension is agitated in contact with a hydrogen atmosphere at room temperatures for 15 minutes, after which there is added 20 parts of 5-benzyloxy-3-{2-[2- 3 ,4 dirnethoxyphenyl -1- (methyl) ethylamino 1 ethyl}indole and 2 parts of oxalic acid. The mixture is again agitated in contact with a hydrogen atmosphere for around 15 hours, after which the catalyst is separated by filtration and the filtrate stripped of solvent by distillation at pressures in the range 2030 mm. The crystalline residue is stirred with ethanol and collected on a filter. The product thus obtained is 5-hydroxy-3-{2-[2-(3,4-dimethoxyphenyl) l-(methyl)ethylamino]ethyl}indole oxalate, which melts at approximately 194. The product has the formula H N W N 00011 HO CHzCHzNHCHCHr H,

I OOOH CH3 (B) hydroxy 3-{2-[2-(3,4-dimethoxyphenyl)-1- (methyl)ethylamino]ethyl}ind0le.A suspension of the oxalate of the foregoing part A of this example in warm aqueous sodium bicarbonate is extracted with benzene, and the benzene solution is thereupon washed with water and stripped of solvent by vacuum distillation. The material which remains is 5-hydroxy-3-{2-[2-(3,4-dimethoxyphenyl) 1 methyl) ethylamino] ethyl}indole.

(C) 5 hydroxy 3-{2-[2-(3,4-dimethoxyphenyl)-1- (methyl)ethylamino]ethyl}indole hydr0chl0ride.--A solution of the free base of the foregoing part B of this example in a minimum quantity of 2-propanol is treated with slightly more than 1 equivalent of hydrogen chloride in 2-propanol. When separation of the precipitate which appears is complete, the mixture is filtered; and the product thus removed is purified by recrystallization from ethanol. In this manner there is obtained 5-hydroxy- 3 {2-[2-(3,4-dimethoxyphenyl) -1-(methyl)ethylamino] ethyl}indole hydrochloride, which melts at approximately 227.

Example 16 5 hydroxy 3 {2 [2 (3,4-dihydroxyphenyl)-1- (methyl) ethylamino] ethyl}indole hydr0chloride.-Substitution of 5 hydroxy-3-{2-[2-(3,4 dimethoxyphenyl)-1- (methyl)ethylamino]ethyl}indole for the 3-{2-[2-(3,4-di methoxyphenyl) 1 (methyl)ethylamino] ethyl}indole called for in the procedure of Example 2(A) affords 5- hydroxy 3 {2-[2-(3,4-dihydroxyphenyl)-1-(methyl) ethylamino]ethyl}indole hydrochloride, which has the formula What is claimed is: 1. A compound of the formula wherein Z and Z areselected from the groupconsisting i I AlkNH-Alk O OH;

OCH;

wherein Alk is an alkylene radical containing more than 1 and fewer than 5 carbon atoms and Alk is an alkylene radical containing more than 1 and fewer than 4 carbon atoms.

3. 3-{2-[2- (3,4 dimethoxyphenyl)-1-(methy1)ethylamino] ethyl}indole.

4. A compound of the formula I l Alk-NH-Alld'QOH wherein Alk is an alkylene radical containing more than 1 and fewer than 5 carbon atoms and Alk is an alkylene radical containing more than 1 and fewer than 4 carbon atoms.

5. 3 {2 [2 (3,4 dihydroxyphenyl) 1 (methyl)- ethylamino] ethyl}indole.

6. A compound of the formula wherein Alk is an alkylene radical containing more than 1 and fewer than 5 carbon atoms and Alk is a hydroxyalkylene radical containing more than 4 carbon atoms.

7. 3 {3 [2 (p hydroxyphenyl)ethylamino]butyl}- indole.

8. A compound of the formula wherein Z is a lower alkoxy radical, Alk is an alkylene radical containing more than 1 and fewer than 5 carbon atoms, and Alk" is an alkylene radical containing'more than 1 and fewer than 4 carbon atoms.

9. 5 benzyloxy 3 {2 [2 3,4 dirnethoxyphenyl)- 1- (methyl) ethylamino] ethyl}indole.

References Cited in the file of this patent UNITED STATES PATENTS 2,708,197 Specter May 10, 1955 2,821,532 Anthony et al. Jan. 28, 1958 2,825,734 Specter Mar. 4, 1958 OTHER REFERENCES Brehm et al.: Jour. Org. Chem, vol. 15, p. 686 (1950). Boyd et al.: Biochem Journal, vol. 29, p. 556 (1935).

, UNITED STATES PATENT OFFICE CERTIFICATE OF CORRECTION Patent No. 2,908 69l October 13 1959 Richard A. Robinson It is hereby certified that error appears in the above numbered patent requiring correction and that the said Letters Patent should read as corrected below.

Column 12, line 4L6 after "than" insert l and fewer than Signed and sealed this 19th day of December 1961,

(SEAL) Attest:

ERNEST W. SWIDER DAVID L. LADD Attesting Officer Commissioner of Patents USCOMM-DC 

1. A COMPOUND OF THE FORMULA 